We propose to 1). Use a set of human schizophrenia (SCZ) disease models utilizing induced pluripotent stem cells (iPSCs) derived from SCZ patients to evaluate six advanced SCZ compounds from a pharma partner, to assess their potential to be further developed into SCZ therapeutics; and 2). Discover new compound leads for SCZ. We will use one of the models - a validated synaptic density screen in 384-well format, using forebrain glutamatergic neurons (FGNs) derived from iPSCs bearing a Disrupted in schizophrenia 1 (DISC1) frameshift mutation. We will characterize the hits in the additional SCZ iPSC models. SCZ affects around 1% of the world's population and is a major public health problem. About 30% of SCZ patients do not response to available medications. 30% only show partial response. The industry's hunt for better therapeutics have been thwarted by inadequacy of current drug discovery models. Patient-specific iPSC-derived neurons hold great promises as effective disease models for mechanism studies and drug discovery. Our team has generated and characterized SCZ iPSC lines from patients with different genetic risk factors and background. These cell lines, isogenic and normal controls will be utilized for this proposal. We have optimized differentiation protocols that produce highly pure populations of cortical neural progenitors (NPCs), GABAergic interneurons and FGNs (>99%, >80% and >90% respectively). The purity of differentiated populations allows us to confidently attribute assay readouts to intrinsic properties of the cellular models and experimental manipulations. The high-throughput synaptic screen is validated: 1). Correcting DISC1 mutation in patient iPSCs corrected the synaptic and other functional defects; 2). Introducing DISC1 mutation into normal iPSCs or mice recreated cellular deficits and created animal behavioral and cognitive deficits; 3). A mechanism relevant compound rescues deficits in both DISC1 FGNs and DISC1 mutant mice; 4). Nine other compounds mechanistically related to this compound was shown to rescue synaptic deficit in a separate targeted screen. Aim 1. Evaluate six advanced discovery/development SCZ compounds from a pharma partner for potential continued development for SCZ. We will differentiate 14 SCZ and control iPSC lines into NPCs and then onto FGNs and GABAergic neurons. Treat the neurons for 2-4 weeks with the six compounds at four concentrations. Assess treatment effects with synaptic screen and other morphological and functional assays. Aim 2. Conduct primary screen of 50,000 compounds with synaptic screen and confirmation screens with additional SCZ iPSC models. We will use synaptic density assay with one DISC1 line for primary screen. We will use its isogenic control and another DISC1 line (with different clinical presentation) for counter and confirmation screens, and further characterize with other SCZ lines to generate leads.